Obesity is a well-known risk factor of multiple metabolic disorders. Importantly, due to the effects of fetal programming during pregnancy, not only obese mothers but also their offspring are affected. Sirtuin (SIRT) 1 is a metabolism-regulating deacetylase whose activation has been shown to mimic the effects of caloric restriction and ameliorate metabolic disorders associated with obesity. However, in the setting of maternal obesity, the role of fetal/neonatal SIRT1 is yet to be elucidated. In this study, we tested the hypothesis that overexpression of SIRT1 in the fetus is protective to the abnormal fetal metabolic programming induced by maternal high-fat diet (HFD) consumption during pregnancy. Female C57BL/6 wild-type mice (WT, 6 weeks old) were fed either chow or HFD for 6 weeks, then bred with hemizygous transgenic males (SIRT1-tg, Col1a1tm1(CAG-Sirt1)Dsin) to produce WT and SIRT1-tg pups (1:1 ratio). In the genotyped WT offspring, maternal HFD induced a significant reduction of liver SIRT1 mRNA expression in association with increased body weight, fat mass, levels of plasma triglycerides (TG), free fatty acids (P<0.001), as well as glucose intolerance (P<0.05). Maternal HFD also increased liver TG concentration (P<0.001) and the mRNA expression of Sterol regulatory element-binding proteins (SREBP)-1c (P<0.05), while reducing the levels of PPARγ, GLUT1, PGC-1α and SOD2 (P<0.01). By contrast, the genotyped SIRT1-tg male offspring either from Chow- or HFD-fed mothers showed higher SIRT1 expression (P<0.001) in association with lower BW, fat deposition and glucose intolerance compared to the WT controls. Additionally, liver mRNA levels of PPARγ and fatty acid synthase were respectively up- and down-regulated in correlation with SIRT1 overexpression (P<0.01), suggesting a potential protective effect of SIRT1 on metabolic diseases induced by maternal obesity, including type 2 diabetes and hepatic steatosis in the offspring.